The present invention relates to certain pharmacologically active compounds, to pharmaceutical compositions containing certain compounds as active substance and to their use as medicaments. More particularly, it has been found that the derivatives described herein can be used for regulating the meiosis.
Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1n) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. This division, therefore, results in the formation of the haploid germ cells with only 1c DNA.
The meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly. All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty. Thus, from early life the female has a stock of oocytes which is drawn upon until the stock is exhausted. Meiosis in females is not completed until after fertilisation, and results in only one ovum and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces 4 spermatozoa.
Only little is known about the mechanisms which control the initiation of meiosis in the male and in the female. In the occyte, new studies indicate that follicular purines, hypoxanthine or adenosine, could be responsible for meiotic arrest (Downs, S. M. et al. Dev. Biol. 82 (1985) 454-458; Eppig, J. J. et al. Dev. Biol. 119 (1986) 313-321; and Downs, S. M. Mol. Reprod. Dev. 35 (1993), 82-94). The presence of a diffusible meiosis regulating substance was first described by Byskov et al. in a culture system of fetal mouse gonads (Byskov, A. G. et al. in Dev. Biol. 52 (1976), 193-200). A meiosis activating substance, (MAS) was secreted by the fetal mouse ovary in which meiosis was ongoing, and a meiosis preventing substance (MPS) was released from the morphologically differentiated testis with resting, non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the beginning, arrest and resumption of meiosis in the male and in the female germ cells (Byskov, A. G. et al. in The Physiology of Reproduction (eds. Knobil, E. and Neill, J. D., Raven Press, New York (1994)). Clearly, if meiosis can be regulated, reproduction can be controlled. A recent article (Byskov, A. G. et al. in Nature 374 (1995), 559-562) describes the isolation from bull testes and from human follicular fluid of certain sterols that activate oocyte meiosis. Unfortunately, these sterols are rather labile and utilisation of the interesting finding would thus be greatly facilitated if more stable meiosis activating compounds were available.
In Aust. J. Chem. 35 (1982), 629-640, Horn et al. deals with compounds possibly having biological activity (insect moulting hormones). Examples of compounds specifically mentioned therein are 5-cyano-5xcex2cholest-7-en-3-one; 5-cyano-5xcex2cholest-7-en-3xcex2-ol; 5-methyl-5xcex2-cholest-7-en-3-one; 5-methyl-5xcex2-cholest-7-en-3xcex1-ol; and 5-methyl-5xcex2-cholest-7-en-3xcex2-ol.
In Bull. Soc. Chim. Fr. (1971), 2037-2047, Levisalles et al., cholesta-4,8(14)-dien-3-one is described as an intermediate.
In Just. Lieb. Ann. Chem. 542 (1939), 218-224, Windaus et al. mentions cholesta-4,7-dien-3-one; cholesta-4,7-dien-3xcex1-ol; and cholesta-4,7-dien-3xcex2-ol as intermediates.
In Pharm. Bull. 1 (1953), 224-227, Arima mentions cholesta-4,8-dien-3-one as intermediate.
In Lipids 13 (1978), 704 et seq., Kandutsch et al. describes some cholestane derivatives which may be potent inhibitors of sterol synthesis. Compounds specifically mentioned therein are, in FIG. 1, 3xcex2,7xcex1-dihydroxycholest-5-ene; 3xcex2,7xcex2-dihydroxycholest-5-ene; 3xcex2-hydroxycholest-5-en-7-one; 3xcex2-hydroxycholest-7-one; 7xcex1-hydroxycholest-4-en-3-one; in FIG. 2 (compounds 1-5), cholest-3,6-dione; 3xcex2-hydroxycholest-6-one; 3xcex2,6xcex2-dihydroxycholestane; cholest-4-en-3,6-dione; 3xcex2,5xcex1,6xcex2-trihydroxycholestane; in FIG. 3, 3xcex2,5xcex1-dihydroxycholestane; 3xcex2,4xcex2-dihydroxycholest-5-ene; and, in FIG. 4 (compounds 1, 3, 4 and 5), cholest-2-en-6-one; cholest-4,6-dien-3-one; cholest-4,7-dien-3-one; cholest-3,5-dien-7-one.
Danish patent application with publication number 130,992, deals with compounds possibly having progestomimetic properties. Examples of compounds specifically mentioned therein are 19-nor-21-methylpregna-4,9-dien-17xcex1-hydroxy-3,20-dione; 19-nor-21-methyl-pregna-4,9-dien-17xcex1-acetoxy-3,20-dione; 19-nor-21,21-dimethylpregna-4,9-diene-17xcex1-hydroxy-3,20-dione; and 17xcex1-21,21-dimethyl-19-nor-pregna-4,9-dien-3,20-dione.
In the Danish patent application with publication number 136,909, 3xcex1-acetoxy-24-nor-cholan-23-one; 3xcex1-hydroxy-26,27-di-nor-23-trans-5xcex2-cholest-23-en-25-carboxylic acid methyl ester; 3xcex1-hydroxy-26,27-di-nor-5xcex2-cholesta-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-5xcex2-cholesta-25-carboxylic acid methyl ester; 3-keto-4-bromo-26,27-di-nor-5xcex2-cholesta-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-cholest4-en-25-carboxylic acid methyl ester; 3xcex2-acetoxy-26,27-di-nor-cholesta-3,5-dien-25-carboxylic acid methyl ester; 3xcex2-hydroxy-26,27-di-nor-cholest-5-en-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-cholest-4,6-dien-25-carboxylic acid methyl ester; 3xcex2-hydroxy-26,27-di-nor-cholesta-3,5,7-trien-25-carboxylic acid methyl ester; and 3xcex2-hydroxy-26,27-di-nor-cholesta-5,7-dien-25-carboxylic acid methyl ester are mentioned as intermediates.
Danish patent application with publication number 146,390, deals with compounds possibly having pharmacological properties, e.g. an inhibiting action on the production of serum cholesterol. Examples of compounds specifically mentioned therein are 3xcex2,22-di-acetoxycholesta-5-en-25-ol; 3xcex2,22-diacetoxy-25-fluorocholesta-5-ene; 22-hydroxycholesta-5-en-25-fluoro-3xcex2-hemisuccinate; 3xcex2,22-diacetoxy-25-dichlorocholesta-5-ene; 3xcex2,22-dihydroxy-25-chlorocholesta-5-ene; 22-hydroxy-25-chlorocholesta-5-en-3xcex2-hemisuccinate; 3xcex2,22-dihydroxy-25-bromocholesta-5-ene; and 3xcex2,22-dihydroxy-25-fluorocholesta-5-ene.
In the Danish patent applications with publication numbers 156,726 and 156,644, cholenic acid; 3xcex2-acetoxycholesta-5-en-25-des-dimethyl-24-one; 3,24-diacetoxycholesta-25-des-dimethyl-5,23-diene; 3xcex2-acetoxycholesta-25-des-methyl-5-en-24-difluoro-25-one; and 3xcex2-acetoxy-24-difluorocholesta-5,7-dien-25-ol are mentioned as intermediates.
In the Danish patent application with publication number 158,790, 3xcex2-hydroxy-cholest-5-en-24-one; 3xcex2-acetoxycholest-5-en-24-one; 5xcex2-cholest-24-one; 5xcex2-cholestan-24xcex1-homo-24-one; 3xcex1,6xcex1-dihydroxy-5xcex2-cholest-24-one; 3xcex1,6xcex1-diacetoxy-5xcex2-cholest-24-one; 3xcex1,6xcex1-diacetoxy-5xcex2-cholest-24xcex1-homo-24-one; 3xcex1,6xcex1-dihydroxy-5xcex2-cholest-24xcex1,24xcex2-bis-homo-24-one; 3xcex1-hydroxy-5xcex2-cholest-24-one; 3xcex1-acetoxy 5xcex2-cholesta-24-one; 3xcex1-benzoyl-oxy-5xcex2-cholesta-24-one; 3xcex1-ethyloxycarbonyloxy-5xcex2-cholesta-24-one; 3xcex1-hydroxy-5xcex2-cholestan-24xcex1-homo-24-one; 3xcex1-hydroxy-24xcex1,24xcex2-bis-homo-5xcex2-cholestane; 3xcex2-hydroxy-cholesta-5,7-dien-24-one; 3xcex2-acetoxycholesta-5,7-dien-24-one; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene-24-one; and 1xcex1,3xcex2-diacetoxycholesta-5,7-diene-24-one are mentioned as intermediates.
Danish patent application with publication number 159,456, deals with compounds possibly having utility in the treatment of gall diskinese. Examples of compounds specifically mentioned therein are chenodeoxycholic acid; ursodeoxycholic acid; trimebutyn salt of chenodeoxycholic acid; and trimebutyn salt of ursodeoxycholic acid.
In the Danish patent application with publication number 162,648, 3xcex2,25-dihydroxy-cholest-5-en-24-one; 3xcex2-acetoxycholest-5-en-24-one; 3xcex2-acetoxy-25-hydroxycholest-5-en-24-one; 3xcex2,25-dihydroxycholest-5-en-24-one; 3xcex2-hydroxycholest-5-en-24-one; 3xcex2-hydroxy-25-hydroperoxycholest-5-en-24-one; 3xcex2,24,25-trihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxycholest-5-en-24-one; 1xcex1,3xcex2,25-trihydroxycholest-5-en-24-one; 1xcex1,3xcex2,24,25-tetrahydroxycholest-5-en-24-one are mentioned as intermediates.
In the Danish patent application with publication number 165,410, 3xcex1-acetoxy-7xcex1-bromocholest-5-ene; 3xcex1-acetoxycholesta-5,7-diene; and 3xcex1-acetoxy-25-hydroxycholesta-5,7-diene are mentioned as intermediates.
In the Danish patent application with publication number 165,695, 3xcex2,25-dihydroxy-26,27-hexafluorocholest-5-ene; and 1xcex1,3xcex2,25-trihydroxy-26,27-hexafluorocholest-5-ene are mentioned as intermediates for the preparation of vitamin D analogues.
Danish patent application with publication number 167,220 deals with compounds possibly having utility for the treatment of liver disorders. An examples of a compound specifically mentioned therein is 3xcex1,7xcex1,12xcex1,24R,26,27-hexahydroxycholestane.
In U.S. Pat. No. 4,425,274, the compounds 3xcex1-hydroxy-7-cholanic acid; 3xcex1,7xcex1-dihydroxycholanic acid; 3xcex1,7xcex2-dihydroxycholanic acid; and lithium 3xcex1,7xcex2,dihydroxycholanate are described as intgermediates.
In the Norwegian patent application with publication number 144,264, cholesta-1,4,-6-trien-3-one; cholest-5-en-1xcex1,3xcex2-diol; 1xcex1-hydroxycholesta-4,6-diene-3-one; 1xcex1,3xcex2,dihydroxycholest-5-ene; 25-hydroxycholesta-1,4,6-triene-3-one; and 1xcex1,3xcex2-25-trihydroxycholest-5-ene are mentioned as intermediates for the preparation of 1xcex1-hydroxy steroids of the cholestane serie.
Norwegian patent application with publication number 158,423, deals with compounds possibly having utility in the treatment of biliary dyskinesis. An example of a compound specifically mentioned therein is 3xcex1,7xcex2-dihydroxydeoxycholic acid.
In the Norwegian patent application with publication number 162,562, 3xcex1,7xcex1-dihydroxydeoxycholic acid; 7-ketodeoxycholic acid; 3xcex1,7xcex2-dihydroxydeoxycholic acid; cholic acid; 7-ketocholic acid; 3xcex1,7xcex2,12xcex1-cholic acid; and 12-ketocholic acid are mentioned as being intermediates in the preparation of ursodeoxycholanic acid.
In the Norwegian patent application with publication number 162,665, cholic acid; 3xcex1-hydroxy-7-ketocholic acid; 3xcex1,7xcex1-diacetoxycholic acid; 3xcex1,7xcex1-diacetoxy-12-ketocholic acid; 3xcex1,7xcex1-dihydroxydeoxycholic acid; 7-ketodeoxycholic acid; 3xcex1,7xcex2-dihydroxydeoxycholic acid; and 3xcex1,7xcex2-dihydroxy-12-ketocholic acid are mentioned as being intermediates in the preparation of ursodeoxycholanic acid.
In the Norwegian patent application with publication number 303,450, cholic acid; cholic acid methyl ester; 3-acetyicholic acid methyl ester; 3-(2-propenyl)cholic acid methyl ester; 3-(3-hydroxypropyl)cholic acid-3-methyl ester; desoxycholic acid; 12-keto-desoxycholic acid; 3xcex2-acetyloxy-12-keto-desoxycholic acid; 3xcex2-(hydroxyethyloxy)cholic acid methyl ester; 3xcex2-(hydroxypropyloxy)cholic acid methyl ester; 3xcex2-(hydroxybutyloxy)cholic acid methyl ester; 3xcex2-(hydroxypentyloxy)cholic acid methyl ester; 3xcex2-(hydroxyhexyloxy)cholic acid methyl ester; 3xcex2-(hydroxydecanoyloxy)cholic acid methyl ester; 3xcex2-(2-hydroxyethyloxyethyloxy)cholic acid methyl ester; 3xcex2-(2-hydroxypropyloxy)cholic acid methyl ester; 3xcex2-(hydroxyethyloxy)desoxycholic acid methyl ester; 3xcex2-(hydroxypropyloxy)desoxycholic acid methyl ester; 3xcex2-(hydroxypentyloxy)desoxycholic acid methyl ester; 3xcex2-(hydroxydecyloxy)desoxycholic acid methyl ester; 3xcex2-(2-hydroxyethyloxy)chenodesoxycholic acid methyl ester; 3xcex2-(3-hydroxypropyloxy)chenodesoxycholic acid methyl ester; 3xcex2-(5-hydroxypentyloxy)chenodesoxycholic acid methyl ester; 3xcex2-(10-hydroxydecyloxy)chenodesoxycholic acid methyl ester; 3xcex2-(2-hydroxyethyloxy)litocholic acid methyl ester; 3xcex2-(3-hydroxypropyloxy)litocholic acid methyl ester; 3xcex2-(5-hydroxypenthyloxy)lithocholic acid methyl ester; 3xcex2-(10-hydroxydecayloxy)lithocholic acid methyl ester; 3xcex2-(benzyloxyethyloxy)cholic acid methyl ester; 3xcex2-(benzyloxyethyloxy)cholic acid tert.butyl ester; 3xcex2-(2-hydroxyethyloxy)cholic acid tert.butyl ester; 3xcex2-(2-hydroxyethyloxy)-7xcex1,12xcex1-diacetyloxycholic acid methyl ester; and 3xcex2-(propionyloxy)-7xcex1,12xcex1-diacetyloxy-24-carboxylic acid methyl ester are mentioned as intermediates.
In the Swedish patent application with publication number 385,905, chenodeoxycholic acid is mentioned to have utility for the treatment of cholelithiasis and cholic acid is mentioned as an intermediate for the preparation thereof.
Swedish patent application with publication number 402,462 mentions sitosterol which may have medical application, e.g. for the prevention or reduction of absorption of cholesterol in the small intestine, and campesterol is mentioned to lower the effect of sitosterol.
In the Swedish patent application with publication number 413,247, 3xcex1-hydroxycholestane and 3xcex2-hydroxycholestane are mentioned to have antiinflammatoric properties and slightly side effects.
Swedish patent application with publication number 430,508 deals with compounds possibly having pharmacological properties, i.e. inhibition of HMG-CoA reductase and inhibi19tion of the formation of serum cholesterol. Examples of compounds specifically mentioned therein are 25-fluorocholest-5-en-3xcex2,22-diol; 25-chlorocholest-5-en-3xcex2,22-diol; 22-hydroxy-25-fluorocholest-5-en-3xcex2-hemisuccinate; 22-hydroxy-25-chlorocholest-5-en-3xcex2-hemisuccinate; and cholesta-5-en-3xcex2,22,25-triol.
Compounds being known to stimulate the meiosis and being different from the compounds claimed in the present patent application are described in International patent applications having Nos. WO 96/00235, 96127658 and 97/00884 (Novo Nordisk A/S) and 98/55498. In International patent application having No. WO 98/52965, filed on May 11, 1998 and published on Nov. 16, 1998, it is stated that certain 20-aralkyl-5xcex1-pregnan derivatives can be used in the preparation of a medicament for the control of fertility and some of the specific compounds mentioned therein are (3xcex2,5xcex1,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol (example 1); (3xcex2,5xcex1,20R)-4,4,20-trimethyl-21-(3-methylphenyl)pregna-8,14-dien-3-ol (example 2A); and (3xcex2,5xcex1,20R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-3-ol (example 7A).
The compounds described herein have advantages compared with the known compounds.
A main purpose of this invention is to furnish compounds which can be used to regulate meiosis.
One purpose of the present invention is to provide compounds and methods useful for relieving infertility in females and males, particularly in mammals, more particularly in humans.
In a further object, the present invention concerns the use of the compounds of the general formula Ic (stated in the claims, below) for relieving infertility in females and males, particularly in mammals, more particularly in humans.
In a further object of the present invention the compounds of the general formula I are useful as contraceptives in females and males, particularly in mammals, more particularly in humans.
In another embodiment, the invention relates to esters, salts, active metabolites and prodrugs of compound of the general formula Ia.
In still another preferred embodiment, the present invention relates to compounds of the general formula Ib (stated in the claims below) or esters, salts, active metabolites or prodrugs thereof as a medicament.
In a further preferred embodiment, this invention relates to compounds of the general formula Ic (stated in the claims below) or esters, salts, active metabolites or prodrugs thereof in the manufacture of a medicament for use in the regulation of meiosis.
In a further preferred aspect, the present invention relates to the use of a compound of formula Ib/Ic or an ester, salt, active metabolite or prodrug thereof as a medicament, in particular as a medicament foruse in the regulation of meiosis. The compound may be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.
In the present context, the expression xe2x80x9cregulating the meiosisxe2x80x9d is used to indicate that certain of the compounds of formula Ia, Ib or Ic can be used for stimulating the meiosis in vitro, in vivo, or ex vivo. Thus, the compounds of formula Ia, Ib or Ic which may be agonists of a naturally occurring meiosis activating substance, can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in females and in males. Other compounds of formula Ia, Ib or Ic, which may be antagonists of a naturally occurring meiosis activating substance, can be used for regulating the meiosis, preferably in vivo, in a way which makes them suited as contraceptives. In this case the xe2x80x9cregulationxe2x80x9d means partial or total inhibition.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof in the regulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic organ ester, salt, active metabolite or prodrug thereof in the stimulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof in the inhibition of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof in the regulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof in the stimulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof in the inhibition of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a yet still further preferred aspect, the present invention relates to a method of regulating the meiosis in a mammalian germ cell which method comprises administering an effective amount of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof to a germ cell in need of such a treatment.
In a still further aspect, the present invention relates to a method of regulating the meiosis in a mammalian germ cell wherein a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof is administered to the germ cell by administering the compound to a mammal hosting said cell.
In a still further aspect, the present invention relates to a method wherein the germ cell the meiosis of which is to be regulated by means of a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof is an oocyte.
In a still further aspect, the present invention relates to a method of regulating the meiosis in an oocyte wherein a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof is administered to the oocyte ex vivo.
In a still further aspect, the present invention relates to a method of regulating the meiosis of a male germ cell by administering a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof to the cell.
In a still further aspect, the present invention relates to a method whereby mature male germ cells are produced by administering in vivo or in vitro a compound of formula Ic or an ester, salt, active metabolite or prodrug thereof to testicular tissue containing immature cells.
In a still further aspect, the present invention relates to compounds of formula Ia, Ib and Ic having improved stability.
According to the present invention there are provided novel compounds of formula Ia (stated in claim 1, below) with interesting pharmacological properties. The compounds described herein are useful for regulating the meiosis in oocytes and in male germ cells.
It has, surprisingly, been found that compounds having a side chain (R22) which is different from the cholesterol and lanosterol side chains or compounds having certain specifically elected substituents in the ring system, have superior properties.
Preferred compounds of formula Ia, Ib and Ic are such having a double bond.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is methyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is hydroxy
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2, together with
R3, designates an additional bond between the carbon atoms at which R2 and R3 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 is C1-C8 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 is C1-C3 alkoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is alkoxy, aralkyloxy, alkoxyalkoxy or alkanoyloxyalkyl, each group comprising a total of up to 10 carbon atoms, preferably up to 8 carbon atoms.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is C1-C4 alkoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is methoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is ethoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is CH3OCH2Oxe2x80x94.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is pivaloyloxymethoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is an acyloxy group derived from an acid having from 1 to 20 carbon atoms.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is an acyloxy group selected from the group comprising acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemi succinoyloxy, hemi glutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxycarbonyloxy, tert-butoxycarbonyloxy and ethoxycarbonyloxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is sulphonyloxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is phosphonyloxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 together with Rxe2x80x23 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is the group xe2x95x90NOH.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is a group of the general formula xe2x95x90NOR38, wherein R38 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is perfluoro(lower alkyl), preferably perfluoro(lower alkyl) having 1 through 6, preferably 1 through 3, carbon atoms in the alkyl group, more preferred trifluoromethyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 and Rxe2x80x24 are both hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein one of R4 and Rxe2x80x24 is hydrogen while the other is methyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 and Rxe2x80x24 are both methyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is branched or unbranched C1-C6 alkyl, optionally substituted by halogen, hydroxy or cyano.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x24 is branched or unbranched C1-C6 alkyl, optionally substituted by halogen, hydroxy or cyano.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is hydroxy and R4 is selected from the group comprising hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x24 is hydroxy and R4 is selected from the group comprising hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 and Rxe2x80x24 together designate methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 and Rxe2x80x24 together with the carbon atom to which they are bound, form a cyclopropane ring.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 and Rxe2x80x24 together with the carbon atom to which they are bound, form a cyclopentane ring.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 and Rxe2x80x24 together with the carbon atom to which they are bound, form a cyclohexane ring.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is alkyl with 1 through 3 carbon atoms, preferably methyl, cyano or hydroxymethyl, or R5 is, together with R4, a methano bridge or R5 is, together with R4, an additional bond.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is a primary or secondary amide derived from a carboxylic acid.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is an ester with a C1-C6-alcohol group.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R6 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R6 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R6 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R6 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R6, together with R5, designates an additional bond between the carbon atoms at which R5 and R6 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is methoxy or acetoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is the group xe2x95x90NOH.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 is a group of the general formula xe2x95x90NOR36, wherein R36 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7 simultaneously is hydroxy and C1-C4 alkyl both being bound to the same carbon atom of the sterol skeleton, i.e. in the 7 position.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7, together with R9, designates an additional bond between the carbon atoms at which R7 and R6 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R7, together with R8, designates an additional bond between the carbon atoms at which R7 and R8 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R8, together with R9, designates an additional bond between the carbon atoms at which R8 and R9 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R8 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R8 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R8 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R9 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R9 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R9 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is methoxy or acetoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is the group xe2x95x90NOH.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is a group of the general formula xe2x95x90NOR37, wherein R37 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 simultaneously is hydroxy and C1-C4 alkyl both being bound to the same carbon atom of the sterno skeleton, i.e. in the 11 position.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11, together with R9, designates an additional bond between the carbon atoms at which R11 and R9 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R11, together with R12, designates an additional bond between the carbon atoms at which R11 and R12 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is C1-C4 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is methoxy or acetoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is the group xe2x95x90NOH.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is a group of the general formula xe2x95x90NOR33, wherein R33 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R14 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R14 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R14, together with R8, designates an additional bond between the carbon atoms at which R14 and R8 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is C1-C4 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is methoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is oxa.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is the group xe2x95x90NOH.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is a group of the general formula xe2x95x90NOR32, wherein R32 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R15, together with R14, designates an additional bond between the carbon atoms at which R15 and R14 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is methoxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is the group xe2x95x90NOH.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is a group of the general formula xe2x95x90NOR34, wherein R34 is C1-C3 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 together with R17, designates an additional bond between the carbon atoms at which R16 and R17 are placed.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R17 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R17 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R17 is in the xcex1 position.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R20 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R20 is hydroxymethyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R20 is C1-C4 alkyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R20 together with Rxe2x80x220 designates methylene.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R20 together with Rxe2x80x220 designates oxo.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x220 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x220 is halogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x220 is methyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x220 is hydroxy.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R22 is cyclohexyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen, amino, cyano, carboxy, a group of the general formula xe2x80x94COOR39, oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio; cyclohexylalkyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, lower alkoxy, halogen, amino, cyano, carboxy, a group of the general formula xe2x80x94COOR39, oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;
alkyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen, amino, cyano, carboxy, a group of the general formula xe2x80x94COOR39, oxo, N-acylamino, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio; or
alkenyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, lower alkoxy, halogen, amino, cyano, carboxy, a group of the general formula xe2x80x94COOR39, oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;
and R39 represents lower alkyl or aralkyl, e.g. benzyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R22 is phenyl, cyclohexyl, benzyl, o-tolyl, m-tolyl, p-tolyl, but-3-enyl, 3-methylbut-3-enyl, 2-methylpropyl, 2-oxo-2-ethoxyethyl, 2-oxo-2-(N,N-dimethylamino)ethyl, carboxymethyl, 3-hydroxymethylbutyl, 2-cyanoethyl, cyclohexyl methyl, 3-chloro-3-methylbutyl, 2-(N,N-dimethylamino)-2-cyanoethyl, 2-chloroethyl, 2-iodoethyl, ethyl, 2-phenylethyl, 2-methoxyethyl, 2-benzyloxyethyl or 2-acetoxyethyl.
Other preferred compounds of formula Ia, Ib and Ic are such wherein Rxe2x80x222 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein the side chain in the 17 position (i.e. xe2x80x94C(R20)(Rxe2x80x220)xe2x80x94CH(R22)(Rxe2x80x222)) is in the xcex2 position.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 together with R3 is an additional double bond and Rxe2x80x23 is hydrogen.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is hydrogen, halogen, methyl, hydroxy or oxo; R2 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R2 designates, together with R3, an additional bond between the carbon atoms at which R2 and R3 are placed; R3 is selected from the group comprising hydrogen, hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkyl and a group of the general formula xe2x95x90NOR38 wherein R38 is hydrogen or C1-C3 alkyl, or R3 designates, together with R2, an additional bond between the carbon atoms at which R2 and R3 are placed; wherein R4 and R4xe2x80x2, which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R4 and R4xe2x80x2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R5 is hydrogen, halogen or hydroxy, or R5 designates, together with R6, an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen, hydroxy, halogen or oxo, or R6 designates, together with R5 or R7, an additional bond between the carbon atoms at which R6 and R5 or R7 are placed; R7 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkyl and a group of the general formula xe2x95x90NOR36 wherein R36 is hydrogen or C1-C3 alkyl, or R7 designates, together with R6 or R8, an additional bond between the carbon atoms at which R7 and R6 or R8 are placed; R8 is hydrogen, hydroxy or halogen, or R8 designates, together with R7, R9 or R14, an additional bond between the carbon atoms at which R8 and R7, R9 or R14 are placed; R9 is hydrogen, hydroxy or halogen, or R9 designates, together with R8 or R11, an additional bond between the carbon atoms at which R9 and R8 or R11 are placed; R11 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkyl and a group of the general formula xe2x95x90NOR37 wherein R37 is hydrogen or C1-C3 alkyl, or R11 designates, together with R9 or R12, an additional bond between the carbon atoms at which R11 and R9 or R12 are placed; R12 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and a group of the general formula xe2x95x90NOR33 wherein R33 is hydrogen or C1-C3 alkyl, or R12 designates, together with R11, an additional bond between the carbon atoms at which R11 and R12 are placed; R14 is hydrogen or hydroxy, or R14 designates, together with R15, an additional bond between the carbon atoms at which R14 and R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and a group of the general formula xe2x95x90NOR32 wherein R32 is hydrogen or C1-C3 alkyl, or R15 designates, together with R14 an additional bond between the carbon atoms at which R15 and R14 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and a group of the general formula xe2x95x90NOR34 wherein R34 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at Which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R20 is selected from the group comprising hydrogen, C1-C4 alkyl and hydroxymethyl, or R20 and R20xe2x80x2 together designate methylene or oxo; R20xe2x80x2 is hydrogen, halogen, alkyl or hydroxy, R220xe2x80x2 is hydrogen, hydroxy or oxo; R22 represents phenyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen (chloro, bromo or iodo), amino, N-alkylamino, N,N-dialkylamino, cyano, carboxy or oxo; benzyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen (chloro, bromo or iodo), amino, N-alkylamino, N,N-dialkylamino, cyano, carboxy or oxo; cyclohexyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen (chloro, bromo or iodo), amino, N-alkylamino, N,N-dialkylamino, cyano, carboxy or oxo; cyclohexylalkyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen (chloro, bromo or iodo), amino, N-alkylamino, N,N-dialkylamino, cyano, carboxy or oxo; alkyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen (chloro, bromo or iodo), amino, N-alkylamino, N,N-dialkylamino, cyano, carboxy or oxo; alkenyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen (chloro, bromo or iodo), amino, N-alkylamino, N,N-dialkylamino, cyano, carboxy or oxo; and esters thereof.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R1, R2, Rxe2x80x24, R5, R11, R12, R15, R16, Rxe2x80x220 and Rxe2x80x222 is each hydrogen, R3 is hydrogen, lower alkyl or perfluoro(lower alkyl), Rxe2x80x23 is hydroxy, or R3 designates, together with Rxe2x80x23, oxo, R4is hydrogen or together with R5 a methano bridge or together with R5 an additional bond, R5 is lower alkyl, cyano, hydroxymethyl, a carbaldehyde, an oxime derived from a carbaldehyde, a carboxylic acid, a primary or secondary amide derived from a carboxylic acid, an ester with a C1-C6-alcohol group or together with R4 a methano bridge or together with R4 an additional bond, R7 is together with R8 an additional bond or hydrogen, if R8 and R9 or R8 and R14 stand together for an additional bond, R8 is together with R7 or with R9 or with R14 an additional bond, R9 is together with R8 an additional bond or a hydrogen atom, if R7 and R8 or R8 and R14 stand together for an additional bond, R14 is, together with R8, an additional bond or a hydrogen atom, if R7 and R8 or R8 and R9 stand together for an additional bond, R17 is hydrogen in the alpha position, R19 is methyl in the beta position, R20 is methyl in the alpha position, and R22 is 3-methylbutyl; and ester, salt, active metabolite or prodrugs thereof.
Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is a C1-C3-alkyl group, preferably a methyl group, a cyano group, a hydroxymethyl group or together with R4 a methano bridge or together with R4 an additional bond.
It is to be understood that the above preferred substituents can be combined in any way with each other.
Examples of interesting and preferred compounds of the general formula Ia, Ib and Ic are as follows:
(20R)-20-Methyl-21-phenyl-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-20-methyl-21-(3-methylphenyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-20-methyl-21-(3-hydroxyphenyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-20-methyl-21-(cyclopentyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; 24-nor-cholest-8,14-dien-3xcex2-ol; (20R)-20-methyl-21-(cyclohexyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-20-methyl-22-phenyl-5xcex1-pregna-8,14-dien-3xcex2-ol; 23,24-dinor-cholest-8,14-dien-3xcex2-ol; (20R)-20-methyl-21-(cyclobutyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methyl-3-methyl-2-butenyl)androsta-8,14-dien-3-xcex2-ol; (20R)-20-methyl-23-dimethylamino-5xcex1-pregna-8,14-dien-3xcex2-ol; 3xcex2,hydroxy-5xcex1-cyanochol-8-en-24-oic acid-N,N-dimethyl amide; 5xcex2-methychol-8-en-3-on-24-oic acid-N,N-dimethyl amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1,14xcex2-chola-8,15-dien-24-oic acid-N,N-dimethyl amide; 3xcex2-hydroxy-5xcex1-cyanocholest-8-en-24-one; 5xcex2-methylchol-8-en-3,24-dione; 3xcex2-hydroxy-4,4-dimethyl-5xcex1,14xcex2-cholesta-8,15-dien-24-one; 3xcex2-hydroxy-5xcex1-cyanochol-8-en-24-oic acid cyclohexyl ester; 5xcex2-methychol-8-en-3-on-24-oic acid cyclohexyl ester; 3xcex2-hydroxy-4,4-dimethyl-5xcex1,14xcex2-chola-8,15-dien-24-oic acid cyclohexyl ester; 3xcex2-hydroxy-5xcex1-chola-8,14-dien-24-oic acid-N-(4-methylpiperazinyl)amide; 3xcex2-hydroxychola-5,7-dien-24-oic acid-N-(4-methylpiperazinyl)amide; 3xcex2-hydroxy-5xcex1-cyanochol-8-en-24-oic acid-N-(4-methylpiperazinyl)amide; 5xcex2-methylchol-8-en-3-on-24-oic acid-N-(4-methylpiperazinyl)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1,14xcex2-chola-8,15-dien-24-oic acid-N-(4-methylpiperazinyl)amide; (20R)-20-methyl-21-phenyl-5xcex1-pregna-5,7-dien-3xcex2-ol; (20R)-20-methyl-21-(3-methylphenyl)-5xcex1-pregna-5,7-dien-3xcex2-ol; (20R)-20-methyl-21-(3-hydroxyphenyl)-5xcex1-pregna-5,7-dien-3xcex2-ol; (20R)-20-methyl-21-(cyclopentyl)-5xcex1-pregna-5,7-dien-3xcex2-ol; 24-nor-cholest-5,7-dien-3xcex2-ol; (20R)-20-methyl-21-(cyclohexyl)-5xcex1-pregna-5,7-dien-3xcex2-ol; (20R)-20-methyl-22-phenyl-5xcex1-pregna-5,7-dien-3xcex2-ol; 23,24-dinor-cholest-5,7-dien-3xcex2-ol; (20R)-20-methyl-21-(cyclobutyl)-5xcex1-pregna-5,7-dien-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methyl-3-methyl-2-butenyl)androsta-5,7-dien-3xcex2-ol; (20R)-20-methyl-23-dimethylamino-5xcex1-pregna-5,7-dien-3xcex2-ol; cholesta-5,7-dien-25-chloro-3xcex2-ol; cholesta-5,7-dien-26-chloro-3-xcex2-ol; cholesta-5,7-dien-26-ol; nor-24-cholesta-8,11-dien-3xcex2-ol; cholesta-4,8-dien-3xcex2-ol; cholesta-4,8-dien-3xcex1-ol; cholesta-4,8(14)-dien-3xcex2-ol; cholesta-4,8(14)-dien-3xcex1-ol; 5-cyano-5xcex1-cholest-7-en-3xcex1-ol; 5-cyano-5xcex1-cholest-7-en-3xcex2-ol; 5-cyano-5xcex2-cholest-7-en-3xcex1-ol; 5-cyano-5xcex1-cholest-8-en-3xcex1-ol; 5-cyano-5xcex1-cholest-8-en-3xcex2-ol; 5-cyano-5xcex2-cholest-8-en-3xcex1-ol; 5-cyano-5xcex2-cholest-8-en-3xcex2-ol; 5-cyano-5xcex1-cholest-8(14)-en-3xcex1-ol; 5-cyano-5xcex1-cholest-8(14)-en-3xcex2-ol; 5-cyano-5xcex2-cholest-8(14)-en-3xcex1-ol; 5-cyano-5xcex2-cholest-8(14)-en-3xcex2-ol; 3xe2x80x2,4xcex1-dihydrocyclopropa[4,5]-5xcex2-cholest-7-en-3xcex2-ol; 3xe2x80x2,4xcex2-dihydrocyclopropa[4,5]-5xcex1-cholest-7-en-3xcex1-ol; 3xe2x80x2,4xcex1-dihydrocyclopropa[4,5]-5xcex2-cholest-8-en-3xcex2-ol; 3xe2x80x2,4xcex2-dihydrocyclopropa[4,5]-5xcex1-cholest-8-en-3xcex1-ol; 3xe2x80x2,4xcex1-dihydrocyclopropa[4,5]-5xcex2-cholest-8(14)-en-3xcex2-ol; 3xe2x80x2,4xcex2-dihydrocyclopropa[4,5]-5xcex1-cholest-8(14)-en-3xcex1-ol; 5-(hydroxymethyl)-5xcex1-cholest-7-en-3xcex2-ol; 5-(hydroxymethyl)-5xcex2-cholest-7-en-3xcex1-ol; 5-(hydroxymethyl)-5xcex1-cholest-8-en-3xcex2-ol; 5-(hydroxymethyl)-5xcex2-cholest-8-en-3xcex1-ol; 5-(hydroxymethyl)-5xcex1-cholest-8(14)-en-3xcex2-ol; 5-(hydroxymethyl)-5xcex2-cholest-8(14)-en-3xcex1-ol; 5-methyl-5xcex2-cholest-8-en-3-one; 5-methyl-5xcex2-cholest-8-en-3xcex2-ol; 5-methyl-5xcex2-cholest-8-en-3xcex1-ol; 5-methyl-5xcex2-cholest-8(14)-en-3-one; 5-methyl-5xcex2-cholest-8(14)-en-3xcex2-ol; 5-methyl-5xcex2-cholest-8(14)-en-3xcex1-ol; 3xcex1-(trifluoromethyl)cholesta-4,7-dien-3xcex2-ol; 3xcex2-(trifluoromethyl)cholesta-4,7-dien-3xcex1-ol; 3xcex1-(trifluoromethyl)cholesta-4,8-dien-3xcex2-ol; 3xcex2-(trifluoromethyl)cholesta-4,8-dien-3xcex1-ol; 3xcex1-(trifluoromethyl)cholesta-4,8(14)-dien-3xcex2-ol; 3xcex2-(trifluoromethyl)cholesta-4,8(14)-dien-3xcex1-ol; 5-methyl-24-nor-5xcex2-cholest-8(14)-en-3-one; (20R)-5,20-dimethyl-21-phenyl-5xcex2-pregn-8(14)-en-3-one; (20R)-21-cyclohexyl-5,20-dimethyl-5xcex2-pregn-8(14)-en-3-one; 5-methyl-24-nor-5xcex2-cholesta-8(14),23-dien-3-one; 4,4-dimethyl-24-benzoylamido-5xcex1-chola-8,14-dien-3xcex2-ol; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid N-phenylalanine amide; mono(3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien)-24 succinate; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid (1-methyl-4-hydroxypiperidinyl)ester; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(norleucine)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(arginine)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(glutamic acid)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(leucine)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid methyl ester; 3xcex2-hydroxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid ethyl ester; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid cyclohexyl ester; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-cholesta-8,14-dien-24-one; 3xcex2-hydroxy-4,4,24-trimethyl-5xcex1-chola-8,14-dien-24-one; 3xcex2-hydroxy-4,4-dimethyl-24-phenyl-5xcex1-chola-8,14-dien-24-one; 3xcex2-hydroxy-4,4-di-methyl-24-(3-pentyl)-5xcex1-chola-8,14-dien-24-one; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-phenyl amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid amide; 4,4-dimethyl-24-phenylamino-5xcex1-chola-8,14-dien-3xcex2-ol; 4,4-dimethyl-24-amino-5xcex1-chola-8,14-dien-3xcex2-ol; 4,4-dimethyl-5xcex1-chola-8,14-dien-3,24-diol; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-aldehyde; 4,4-dimethyl-17xcex2-((1R)-methyl-4-methyl-3-pentenyl)androsta-8,14-dien-3xcex2-ol; 4,4-dimethyl-5xcex1-cholesta-14,16,24-triene-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methyl-3-methyl-2-butenyl)androsta-8,14-dien-3xcex2-ol; (20R)-4,4,20-trimethyl-21-(4-methylphenyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-4,4,20-trimethyl-21-(2-methylphenyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-4,4,20-trimethyl-21-(cyclohexyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-4,4,20-trimethyl-21-(3-hydroxyphenyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-4,4,20-trimethyl-22-(cyclohexyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; 24-nor-4,4-dimethyl-5xcex1-cholest-8,14-dien-3xcex2-ol; 27-nor-4,4-dimethyl-5xcex1-cholest-8,14,25-trien-3xcex2-ol; (20R)-4,4,20-trimethyl-21-(cyclobutyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; (20R)-4,4,20-trimethyl-21-(cyclopentyl)-5xcex1-pregna-8,14-dien-3xcex2-ol; 25-chloro-4,4-dimethyl-5xcex1-cholesta-8,14-dien-3xcex2-ol; 4,4-dimethyl-24-(N,N-dimethylamino)-24-cyano-5xcex1-cholesta-8,14-dien-3xcex2-ol; 4,4-dimethylcholest-8,14,25-trien-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methyl-4-iodobutyl)androsta-8,14-dien-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methylbutyl)androsta-8,14-dien-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methyl-4-cyanobutyl)androsta-8,14-dien-3xcex2-ol; 4,4-dimethyl-17xcex2-((1R)-methyl-4-cyanobutyl)androsta-8,14-dien-3xcex2-ol; 27-nor-3xcex2-hydroxy-4,4-dimethyl-5xcex1-cholesta-8,14-dien-26-oic acid benzyl ester; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(methionine methyl ester)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(methionine)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(4-methylpiperazinyl)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-tert-butylamide; 3,xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(isonipecotic acid ethyl ester)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(isonipecotic acid)amide; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid-N-(phenylalanine methyl ester)amide; 3xcex2-hydroxy-4,4-dimethylchola-5,7-dien-24-oic acid; 3xcex2-hydroxy-4,4-dimethylchola-5,7-dien-24-oic acid-N-dimethyl amide; 4,4-dimethyl-24-acetamido-5xcex1-chola-8,14-dien-3xcex2-ol; 4,4-dimethyl-24-acetoxy-5xcex1-chola-8,14-dien-3xcex2-ol; 4,4-dimethyl-24-methoxy-5xcex1-chola-8,14-dien-3xcex2-ol; 4,4-dimethyl-24-benzyloxy-5xcex1-chola-8,14-dien-3xcex2-ol; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-chola-8,14-dien-24-oic acid benzyl ester; 26,27-diethyl-3xcex2-hydroxy-4,4-dimethyl-5xcex1-cholesta-8,14-dien-26,27-dioate; 3xcex2-hydroxy-4,4-dimethyl-5xcex1-cholesta-8,14-dien-26,27-dioic acid; and 27-nor-3xcex2-hydroxy-4,4-dimethyl-5xcex1-cholesta-8,14-dien-26-oic acid.
Preferred compounds of formula Ia, Ib and Ic are such which when tested by the method described below for agonistic properties (example 71) shows a relative activity of at least 50, preferably at least 80, or when tested by the method described below for antagonistic properties (example 72) shows a IC50 value below 10, preferably below 2.
Examples of other preferred compounds are such not being active at the oestrogen receptor, and preferably compounds not being active at other hormone receptors.
Further preferred embodiments are mentioned in the appended claims.
As used in the present description and claims, a lower alkyl groupxe2x80x94when used alone or in combinationsxe2x80x94may be a straight or branched alkyl group. Preferably, said alkyl group contains not more than 6 carbon atoms. Examples of preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, more preferred methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, still more preferred methyl and ethyl. In a preferred embodiment of this invention, the alkyl group contains not more than 4 carbon atoms, preferably not more than 3 carbon atoms.
As used in the present description and claims, alkoxy designates a straight or branched alkoxy group, preferably containing not more than 6 carbon atoms, preferably not more than 4 carbon atoms, most preferred not more than 3 carbon atoms. Examples of preferred alkoxy groups are methoxy, ethoxy and propoxy, more preferred methoxy and ethoxy.
As used in the present description and claims, N-alkylamino is an alkyl group connected to an amino group. Preferably, said alkyl group is a lower alkyl group as defined above. Preferred N-alkylamino groups are methylamino and ethylamino.
As used in the present description and claims, N,N-alkylamino is two alkyl group which are the same or different and which are connected to an amino group. Preferably, said alkyl group are lower alkyl groups as defined above. Preferred N,N-alkylamino groups are N,N-dimethylamino, N,N-diethylamino and N-methyl-N-ethylamino.
As used in the present description and claims, the expression alkenyl designates a straight or branched alkenyl group preferably containing not more than 6 carbon atoms, preferably not more than 3 carbon atoms.
As used in the present description and claims, the expression halogen preferably designates chloro, bromo or iodide. Another group of preferred halogens are fluoro and chloro, preferably fluoro.
As used in the present description and claims, the expression C3-C6 cycloalkyl designates a cycloalkyl group containing 3 through 6 carbon atoms in the ring. Preferred examples are cyclopropyl and cyclopentyl.
As used in the present description and claims, the expression acyloxy designates a monovalent substituent comprising an optionally substituted C1-6-alkyl or phenyl group linked through a carbonyloxy group; such as e.g. acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, benzoyl and the like. Optionally said acyloxy group may contain a hydroxy and/or carboxy group.
As used in the present description and claims, a statement that, e.g., R1 is oxo means that oxo (xe2x95x90O) is present in the 1 position and, consequently, there is no hydrogen atom in the 1 position. Analogous considerations apply for similar situations. In other instances, two symbols together may represent oxo, e.g., R3 and Rxe2x80x23.
As used in the present description and claims, a statement that, e.g., R12 is methylene means that methylene (xe2x95x90CH2) is present in the 12 position and, consequently, there is no hydrogen atom in this position. Analogous considerations apply for similar situations. In other instances, two symbols together may represent methylene, e.g., R4 and Rxe2x80x24.
As used in the present description and claims, a statement that alkoxy is optionally substituted (R3) means that the alkoxy group is substituted with a convenient substituent such as hydroxy or carboxy.
As used in the present description and claims, the expressions xe2x80x9ca primary or secondary amide derived from a carboxylic acidxe2x80x9d used for the substituent R5 is a group of the general formula xe2x80x94CONHR40 wherein R40 is hydrogen or lower alkyl.
As used in the present description and claims, the expressions xe2x80x9can ester with a C1-C6-alcohol groupxe2x80x9d used for the substituent R5 is a group of the general formula xe2x80x94COOR41 wherein R41 is lower alkyl or aralkyl.
As used in the present description and claims, the expression arakyl designates alkyl substituted by an aryl group, e.g. benzyl.
Salts of compounds of formula Ia, Ib and Ic are preferably pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66 (1977), 2 et seq.
Esters of compounds of formula Ia, Ib and Ic are formally derived by esterification of one or more hydroxylic groups of a compound of formula Ia, Ib or Ic, respectively, with an acid which can for example be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulphamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.
A xe2x80x9cmetabolitexe2x80x9d of a compound of formula Ia, Ib or Ic is an active derivative of a compound of formula Ia, Ib or Ic which is produced when the compound of formula Ia, Ib or Ic is metabolised. Metabolites of compounds of formula Ia, Ib or Ic can be identified either by administration of a compound of formula Ia, Ib or Ic to a host and an analysis of blood samples from the host, or by incubation of a compound of formula Ia, Ib or Ic with hepatic cells in vitro and analysis of the incubant.
A xe2x80x9cprodrugxe2x80x9d is a compound that either is converted into a compound of formula Ia, Ib or Ic in vivo or which has the same active metabolites as a compound of formula Ia, Ib or Ic.
The compounds of formula Ia, Ib or Ic have a number of chiral centres in the molecule and thus exists in several isomeric forms. All these isomeric forms and mixtures thereof are within the scope of the invention.
The compounds of the general formula Ia, Ib and Ic can be prepared analogously with the preparation of known compounds. Hence, synthesis of the compounds of formula Ia, Ib and Ic can followed the well established synthetic pathways described in the comprehensive sterol and steroid literature. The following books can be used as the key source in the synthesis: L. F. Fieser and M. Fieser: Steroids: Reinhold Publishing Corporation, NY 1959; Rood""s Chemistry of Carbon Compounds (editor S. Coffrey): Elsevier Publishing Company, 1971; J. Fried and J. A. Edwards: Organic Reactions in Steroid Chemistry, Vol. I and II, Van Nostrand Reinhold Company, New York, 1972; and especially Dictionary of Steriods (editors: R. A. Hill; D. N. Kirk; H. L. J. Makin and G. M. Murphy): Chapmann and Hall. The last one contains an extensive list of citations to the original papers covering the period up to 1990. All these books including the last mentioned citations are incorporated by reference. In addition, information in all the above publications (including patent specifications) dealing with preparation of compounds similar with compounds of formula Ia, Ib and Ic is incorporated by reference.
Particularly, the compounds of the present invention may be synthesised according to the following general procedures:
Cholesta-5,8-dien-3-ol 1, which is synthesised as described in the literature [J. Lip. Res. 37, 1529, (1996)], can be oxidised in an Oppenauer reaction to give cholesta-4,8-dien-3-one 2 (scheme 1). In this reaction, the sterol is treated with a ketone like acetone, quinone or cyclohexanone in the presence of aluminum isopropoxide or aluminum tert-butoxide [e.g. J. Chem. Soc. Perkin 12667 (1994)]. The sterol can also be oxidised with pyridinium dichromate [vide Synth. Commun. 20 (1990), 1167]. The same oxidation reaction can be carried out with cholesta-5,8(14)-dien-3xcex2-ol, which is also synthesised as described in the literature [J. Lip. Res. 37 (1996), 1529,] to give cholesta-5,8(14)-dien-3-one. For this ketone, a laborious synthesis is described in the literature [Bull. Soc. Chim. Fr. 2037, (1971)]. Cholesta-4,7-dien-3-one is synthesised according to literature procedures [Liebigs Ann. Chem. 542 (1939), 218,] (in scheme 1, the series with the xcex948-double bond are shown as an example, analogous reactions have to be performed in the xcex947- and xcex948(14)-series).
In the following, only the syntheses in the xcex948-series are described. The derivatives in the xcex947 and xcex948(14)-series can be synthesised by a skilled artisan from the corresponding starting materials in the same way. 
Enone 2 can be treated with different C1-C6-Grignard reagents to give two diastereomeric alcohols 3 and 4 (with R3=C1-C6-alkyl), which are easily separated by column chromatography [e.g. J. Med. Chem. 40 (1997), 61].
Cholesta-4,8-dien-3-one 2 can be reduced according to well known literature procedures. Lithium aluminum hydride, sodium borohydride and diisobutylaluminum hydride are especially useful [e.g. Liebigs Ann. Chem. 542 (1939), 218]. Two diastereomeric alcohols of the formulae 3 and 4 (with R3=hydrogen) can be obtained and readily separated by column chromatography.
For the introduction of perfluoroalkyl substituents in position 3, cholesta-4,8-dien-3-one 2 can be treated with perfluoroalkyltrialkylsilanes in the presence of fluoride sources like tetrabutyl-ammonium fluoride or caesium flouride. The trifluoromethyl group is preferentially introduced with reagents like trimethylsilyltrifluoromethane or triethylsilyltrifluoromethane [J. Org. Chem. 56 (1991), 984; J. Org. Chem. 54 (1989), 2873].
Again two diastereomeric alcohols of the formulae 3 and 4 (with R3 perfluoroalkyl, preferentially: trifluoromethyl) can be obtained and readily separated by column chromatography.
The cyanoketones 5 and 6 are available starting from cholesta-4,8-dien-3-one 2 via a conjugate addition of cyanide (scheme 2). Different reagents like diethylaluminum cyanide [J. Org. Chem. 59 (1994), 2766] and some alkali and earth alkali metal cyanides [Tetrahedron Lett. 28 (1987), 4189; Can. J. Chem. 59 (1981), 1641] can be used in this reaction. 
The readily separated cyanoketones 5 and 6 can be reduced according to well known literature procedures. Lithium aluminum hydride, sodium borohydride and diisobutyl-aluminum hydride are used preferentially [e.g. Aust. J. Chem. 35 (1982), 629]. In the reduction reactions, two diastereomeric alcohols 7 and 8 (R3=H), respectively, 9 and 10 (R3=H) are obtained.
The cyanoketones of the formulae 5 and 6 can also be treated with Grignard reagents [e.g. Chem. Pharm. Bull. 9 (1961), 854] to give two diasteareomeric tertiary alcohols 7 and 8 or 9 and 10 (with R3=C1-C6-alkyl), respectively.
The hydroxymethyl derivatives of the formulae 12 and 14 can be synthesised in two step sequences from the cyanoalcohols 8 and 9, respectively (scheme 3). First the cyano group can be reduced with an electrophilic reducing agent like diisobutylaluminum hydride to give the corresponding imines, which are hydrolysed in situ to the carbaldehydes 11 and 13. In the second step, thecarbaidehydes can be further reduced with well known reducing agents like lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride to the desired hydroxymethyl derivatives [e.g. J. Med. Chem. 39 (1996), 5092]. 
The methano derivatives of the formulae 15 and 16 can be synthesised form the allylic alcohols 3 and 4, respectively (scheme 4). Different variations of the Simmonsmith reaction can be employed. As reagents, diiodomethane in the presence of zinc/copper-couple [e.g. J. Org. Chem. 31 (1966), 3869; J. Med. Chem. 39 (1996), 4218] as well as chloroiodomethane in the presence of a diethylzinc solution [J. Am. Chem. Soc. 108 (1986), 6343] can be used in this cyclopropanation reaction. 
5xcex2-Methylcholest-8-en-3-one 17 can be synthesised from cholesta-4,8-dien-3-one 2 via a conjugate addition reaction (scheme 5). The methyl group is introduced either with lithium dimethylcuprate [e.g. Aust. J. Chem. 35 (1982), 629] or with methyl-Grignard compounds or trimethylaluminum in the presence of nickel catalysts [e.g. Tetrahedron Lett. 35 (1994), 6075; Synthesis 3 (1995), 317]. 
Subsequent reduction of 5xcex2-methylketone 17 is achieved with different well known reducing agents like lithium aluminum hydride, sodium borohydride and diisobutylaluminum hydride [e.g. Aust. J. Chem. 35 (1982), 629]. Two diastereomeric alcohols 18 and 19 (R3=hydrogen) can be obtained and readily separated by column chromatography.
If 5xcex2-methylketone 17 is treated with Grignard reagents, two diastereomeric tertiary alcohols (18 and 19; with R3=C1-C6-alkyl) are obtained, which are easily separated by column chromatography.
Analogues that combine a 5-cyano-substituent with different steroidal sidechains can be synthesized by the following general route (see scheme 6): Starting from lichesterol, which can be synthesized as described in the literature [J. Chem. Soc. Perkin Trans. 1 (1981), 2125], an enone can be generated by an oppenauer oxidation [e.g. J. Chem. Soc. Perkin Trans. 1 (1994), 2667]. A cyano group can be introduced by conjugate addition [J. Org. Chem. 59 (1994), 2766]. After protection of the 3-ketone as an ketal, the side chain can be cleaved by ozonolysis and subsequent reductive work up [Synthesis 3 (1990), 193]. The 22-alcohol can be transformed to the corresponding tosylate to generate the appropriate leaving group for the copper catalyzed addition of grignard reagents. By this addition, different alkyl- and aryl side chains can be intoduced [Chem. Pharm. Bull. 28 (1980), 606]. After deprotection of the ketone, the latter can be reduced to the corresponding xcex1- and xcex2-alcohols by standard methods. 
The compounds of the present invention will influence the meiosis in oocytes as well as in male germ cells.
The existence of a meiosis inducing substance in nature has been known for some time. However, until recently the identity of the meiosis inducing substance or substances was unknown.
The prospects of being able to influence the meiosis are several. According to a preferred embodiment of the present invention, a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof can be used to stimulate the meiosis. According to another preferred embodiment of the present invention, a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof can be used to stimulate the meiosis in humans. Thus, the compounds of formula Ia, Ib or Ic and ester, salt, active metabolite or prodrugs thereof are promising as new fertility regulating agents without the usual side effect on the somatic cells which are known from the hitherto used hormonal contraceptives which are based on estrogens and/or gestagens.
For use as a contraceptive agent in females, a meiosis inducing substance can be administered so as to prematurely induce resumption of meiosis in oocytes while they are still in the growing follicle, before the ovulatory peak of gonadotropins occurs. In women, the resumption of the meiosis can, for example, be induced a week after the preceding menstruation has ceased. When ovulated, the resulting overmature oocytes are then most likely not to be fertilised. The normal menstrual cycle is not likely to be affected. In this connection it is important to notice, that the biosynthesis of progesterone in cultured human granulosa cells (somatic cells of the follicle) is not affected by the presence of a meiosis inducing substance whereas the estrogens and gestagens used in the hitherto used hormonal contraceptives do have an adverse effect on the biosynthesis of progesterone.
According to another aspect of this invention, a meiosis inducing substance of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof can be used in the treatment of certain cases of infertility in females, including women, by administration thereof to females who, due to an insufficient own production of meiosis activating substance, are unable to produce mature oocytes. Also, when in vitro fertilisation is performed, better results can be achieved, when a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof is added to the medium in which the oocytes are cultured.
When infertility in males, including men, is caused by an insufficient own production of the meiosis activating substance and thus a lack of mature sperm cells, administration of a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof may relieve the problem.
As an alternative to the method described above, contraception in females can also be achieved by administration of a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof which inhibits the meiosis, so that no mature cocytes are produced. Similarly, contraception in males can be achieved by administration of a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof which inhibits the meiosis, so that no mature sperm cells are produced.
The route of administration of compositions containing a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof may be any route which effectively transports the active compound to its site of action.
Thus, when the compounds of this invention are to be administered to a mammal, they are conveniently provided in the form of a pharmaceutical composition which comprises at least one compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof in connection with a pharmaceutically acceptable carrier. For oral use, such compositions are preferably in the form of capsules or tablets.
From the above it will be understood that administrative regimen called for will depend on the condition to be treated. Thus, when used in the treatment of infertility, the administration may have to take place once only, or for a limited period, e.g. until pregnancy is achieved. When used as a contraceptive, the compounds of formula Ia, Ib or Ic or ester, salt, active metabolite or prodrugs thereof will either have to be administered continuously or cyclically. When used as a contraceptive by females and not taken continuously, the timing of the administration relative to the ovulation will be important.
Pharmaceutical Compositions
Pharmaceutical compositions comprising a compound of formula Ia, Ib or Ic or an ester, salt, active metabolite or prodrug thereof may further comprise carriers, diluents, absorption enhancers, preservatives, buffers, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients which are conventionally used in the art. Examples of solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.
Liquid compositions include sterile solutions, suspensions and emulsions. Such, liquid compositions may be suitable for injection or for use in connection with ex vivo and in vitro fertilisation. The liquid compositions may contain other ingredients which are conventionally used in the art, some of which are mentioned in the list above.
Further, a composition for transdermal administration of a compound of this invention may be provided in the form of a patch and a composition for nasal administration may be provided in the form of a nasal spray in liquid or powder form.
The dose of a compound of formula Ia, Ib or Ic to be used will be determined by a physician and will depend, inter alia, on the particular compound employed, on the route of administration and on the purpose of the use. In general, the compositions of the invention are prepared by intimately bringing into association the active compound with the liquid or solid auxiliary ingredients and then, if necessary, shaping the product into the desired formulation.
Usually, not more than 1000 mg, preferably not more than 100 mg, and in some preferred instances not more than 10 mg, of a compound of formula Ia, Ib or Ic is to be administered to mammals, e.g. to. man, per day.
None of the compounds of formula Ia, Ib and Ic have shown to be toxic when administered to man in an amount of 1000 mg per day.
The compounds of formula Ia, Ib or Ic thereof can be synthesised by methods known per se.